The molecular events underlying synaptic plasticity and behavioral memory are very complex, but can be divided into 2 fundamentally distinct phases: induction, which initiates the plasticity, and maintenance, which sustains it. We have focused on the enzyme protein kinase C (PKC), which has been implicated in both phases of plasticity, by examining the family of PKC isoforms in hippocampal slices during increases in synaptic strength caused by high-frequency tetanic stimulation (long-term potentiation, LTP). Our previous work has established that one isoform, the atypical PKCzeta, is the dominant PKC maintaining LTP. The activation of zeta is through the protein synthesis- dependent formation of its independent catalytic domain, PKMzeta. The critical role of PKMzeta in LTP maintenance, however, does not exclude the possibility that atypical PKC may also have an important early role in LTP induction. While our previous work focused on PKMzeta, additional atypical PKC forms, including the other atypical isozyme, PKCiota, need to be considered. The major objective of this proposal is to examine the role of atypical PKC in LTP induction. The evidence pointing to this hypothesis is as follows: 1) During LTP induction, there is an early activation of atypical PKC by translocation to membrane. 2) Whole-cell perfusion of a dominant negative inhibitor of atypical PKC into CA1 pyramidal cells prevents the early potentiation during LTP induction. 3) Perfusion of active atypical PKC causes synaptic potentiation that occludes the early potentiation induced by tetanic stimulation. Thus our first aim is to determine the mechanisms of activation of atypical PKC during LTP induction. While the late activation in maintenance is through protein synthesis of PKMzeta, the early activation of atypical PKC is through translocation of PKCiota to membrane. Second, we will examine whether the initial activation of atypical PKC during LTP induction leads to early potentiation of synaptic transmission, and the transition to PKMzeta in LTP maintenance. Third, we will examine the direct physiological effects of the different atypical PKC isoforms in synaptic transmission using whole-cell recording, and during behavior in Drosophila. Initial results show that transgenic expression of PKMzeta in flies consolidates transient memory into long-term memory. These 3 aims will provide fundamental knowledge on the role of atypical PKCs in neuronal signaling, and may lead to unifying, evolutionarily conserved molecular mechanisms for synaptic plasticity and behavioral memory.